RU2208616C2 - Method for preparing mometasone furoate - Google Patents

Abstract

FIELD: chemical technology, pharmacy. SUBSTANCE: invention relates to the improved method for preparing the known anti-inflammatory substance mometasone furoate (I). (I) is prepared by direct esterification of 17-hydroxyl group of mometasone using 2-furoyl chloride in the presence of tertiary amine and inert solvent, preferably, dichloromethane without preliminary protection of free 11-hydroxyl group. For removal of formed enolfuroate additional treatment with hydrochloric acid is carried out. EFFECT: improved preparing method. 8 cl

Description

 The invention relates to a method for producing mometasone furoate.

Патент США А-4.472.393 описывает два способа получения фуроата мометазона. В примере 12, способ I в качестве исходного вещества используют 9β, 11β-эпокси-17α, 21-дигидрокси-16α-метил-1,4-прегнадиен-3,20-дион, тогда как в способе II используют 21-хлор-17α-гидрокси-16α-метил-1,4,9(11)-прегнатриен-3,20-дион.Mometasone furoate is well known (Shapiro and Grove, USA 4/472/393 and Kwok, Tsi, Tan and Fu, WO 098/00437) as a strong anti-inflammatory steroid having a structure

US patent A-4.472.393 describes two methods for producing mometasone furoate. In Example 12, method I uses 9β, 11β-epoxy-17α, 21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione as starting material, while 21-chloro-17α is used in method II -hydroxy-16α-methyl-1,4,9 (11) -pregnatriene-3,20-dione.

 WO 98/00437 describes an improved process starting from 9β, 11β-epoxy-17α, 21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione.

 Currently, the inventors have developed a new method for producing mometasone furoate, including complex esterification of the 17-hydroxy group without first protecting the 11-hydroxy group.

 A large number of clinically useful steroids in which the 17-hydroxy group is complexly esterified and the 11-hydroxy group exists in free form are well known as clinically useful corticosteroids. Typically, the ester group is introduced at the 17-position until no other hydroxyl group is present in the molecule, and other free hydroxyl groups are formed or unmasked later during the synthesis. When another hydroxyl group is present, such as an 11-hydroxy group, indirect methods are used. You can enter the 17-ester group by hydrolysis of 17,21-orthoesters or by performing complex esterification after protecting other hydroxyl groups in the molecule. For example, to achieve this, the protection of the 11-hydroxy group in the form of a trihaloacetic ester, in the form of a trialkylsilyl ether or masked in the form of 9.11-epoxide was used.

 In the present method, it was unexpectedly found that the 17-hydroxy group can be difficult to esterify without resorting to the protection of the 11-hydroxy group or to the disguised 11-hydroxy group. In previous practice, the introduction of the 17-furoate group was always carried out with the 9.11-epoxy group present in the molecule, which was later converted to the desired 9α-chloro-11β-hydroxy derivative. Mometasone itself can be obtained in various ways.

It was unexpectedly found that when mometasone is reacted with 2-furoyl chloride in the presence of a tertiary amine in an inert solvent, mometasone 17- (2-furoate) is obtained in good yield. 2-Furoyl chloride should preferably be used in excess, with an amount between 2.5 and 4 molar equivalents being preferred, but amounts outside this range are also acceptable. There is no particular limitation on the nature of the tertiary amine, whose function is to activate 2-furoyl chloride and neutralize the hydrochloric acid released during the reaction, although triethylamine is preferred. The tertiary base is preferably used in excess of 3 to 6 molar equivalents, but larger or smaller than these amounts can be used. The solvent is preferably a non-polar, water-immiscible solvent and should be such that all components of the reaction mixture, especially any activated form of the acylating agent, are in solution during the reaction. It has been found that dichloromethane is a suitable solvent, although other solvents that satisfy the above criteria can be used. The reaction is carried out at low to moderate temperatures, usually from 0 to 25 ^{° C.} over a period of several hours, although higher or lower temperatures can be used, which respectively can either shorten or increase the reaction time. When carrying out the reaction in dichloromethane at 10 ^{° C.} and using triethylamine, it usually passes completely over a period of 10-15 hours.

During the reaction, by-products can form, such as enol furoates at positions 3 and 20. This in no way affects the yield or purity of the final product, since these compounds are easily converted to mometasone furoate by brief treatment with dilute aqueous hydrochloric acid. Typically, after completion of the complex esterification, the reaction solution, after removal of the excess base with a short acid wash, is treated with aqueous hydrochloric acid for several hours to convert the by-products into the target mometasone furoate. This treatment can be carried out in a two-phase system at a temperature of from 10 to 25 ^o With, although other temperatures can be used. In order to reduce the reaction time, thorough mixing and the use of a large volume of aqueous hydrochloric acid are preferred to ensure that large surface areas of the two phases are in contact.

Alternatively, an organic solvent mixed with both water and a reaction solvent can be added to increase the concentration of hydrochloric acid in the organic phase. For example, for this purpose, either ethanol or acetic acid can be used in a proportion of 0.5 to 2 volumes, in which case the reaction time at 25 ^{° C. is} usually 3 to 5 hours.

 Mometasone furoate can be isolated using standard techniques. Water washings are used to remove water-soluble materials, after which dichloromethane is replaced with a low molecular weight alcohol, such as methanol or ethanol, from which the product crystallizes in pure form and in high yield. Additional methods of recrystallization from a number of other solvents suitable for the purification of pharmaceutical products such as acetone, methanol and ethanol can be carried out.

 The following example illustrates, but in no way limits the present invention.

EXAMPLE
Obtaining 17- (2-furoate) mometasone
Mometazone (30 g) was suspended in methylene chloride (300 ml) and the resulting suspension was cooled to 0-5 ^° C. Triethylamine (57 ml) was added at this temperature. Then 2-furoyl chloride (24 ml) was slowly added at a temperature of 510 ^° C. The mixture was then stirred at 8 -12 ^{° C.} until the level of mometasone present was lower than 0.2% according to HPLC. The reaction solution was then cooled to a temperature between -5 and 5 ^° C, and water (120 ml) was added with stirring. After stirring for 1 h at a temperature of 10 to 15 ^{° C., the} mixture was cooled to a temperature between 0 ^° and 5 ^{° C.} and concentrated hydrochloric acid was added to adjust the pH of the aqueous layer between 1 and 2.

The phases were separated and the aqueous layer was extracted with methylene chloride (60 ml). Concentrated hydrochloric acid (90 ml) and acetic acid (30 ml) are added to the combined organic layers at a temperature between 15 and 25 ^° C. Then, the two-phase reaction mixture is stirred at 20-25 ^{° C.} until less than 0 remains. , 1% by-products according to HPLC. The reaction mixture is cooled to a temperature of 0 to 5 ^{° C.} and water (120 ml) is added. The lower organic layer was separated and water (120 ml) and 8 N were added. an aqueous solution of sodium hydroxide (about 30 ml) to bring the pH to between 5 and 6. After stirring for 2 hours, the organic layer was separated and washed with water (120 ml).

The organic solution (containing 17- (2-furoate) -methasone) was concentrated by distillation to a volume of 120 ml. Additional methanol (120 ml) was added and the mixture was concentrated to 120 ml. This procedure is repeated two more times. The reaction mixture is slowly cooled to a temperature between 20 and 25 ^o C, then cooled to a temperature between 0 and 5 ^o C and stirred for 2 hours. Then, crude 17- (2-furoate) mometasone is filtered off and washed with cold methanol (0-5 ^o C, 2 • 24 ml).

Purification of 17- (2-furoate) mometasone
The wet cake was dissolved in acetone (395 ml) and charcoal (3 g) was added. After stirring at 15-25 ^{° C.} for at least 24 hours, the charcoal is filtered off and washed with acetone (90 ml). Charcoal (3 g) was added to the solution, and the solution was stirred at a temperature between 15 ^{° C.} and 25 ^{° C.} for at least 24 hours. The charcoal was then filtered off and washed with acetone (75 ml).

 The solution was concentrated by distillation to a volume of 120 ml. During this concentration, 17- (2-furoate) mometasone begins to crystallize. Methanol (120 ml) was added and the solution was again concentrated to 120 ml. This procedure is repeated twice.

The suspension is slowly cooled to a temperature between 20 and 25 ^o C, then cooled to a temperature between 0 and 5 ^o C and stirred for about 2 hours at this temperature. Then pure 17- (2-furoate) -methasone is filtered off and washed with cold methanol (0-5 ^° C, 2 • 24 ml). The product is dried at 60 -70 ^o C. Receive a yield of 29.92 g

Claims (8)

 1. A method of producing mometasone furoate, which includes the reaction of mometasone with 2-furoyl chloride in the presence of a tertiary amine in an inert solvent.  2. The method according to claim 1, in which the tertiary amine is triethylamine.  3. The method according to claim 1, in which the solvent is a non-polar water-immiscible solvent, such that any activated form of 2-furoyl chloride is in solution during the reaction.  4. The method according to claim 1 or 3, in which the inert solvent is dichloromethane.  5. The method according to any one of the preceding paragraphs, which use from 2.5 to 4 molar equivalents of 2-furoyl chloride per molar equivalent of mometasone.  6. The method according to any one of the preceding paragraphs, which use from 3 to 6 molar equivalents of triethylamine per molar equivalent of mometasone. 7. The method according to any one of the preceding paragraphs, in which the reaction is carried out at a temperature of from 0 to 25 ^o C.  8. The method according to any one of the preceding paragraphs, further comprising processing the reaction products with aqueous hydrochloric acid to remove enolfuroates formed at positions 3 and 20 of mometasone furoate.